The efficacy of many bioactive agents is predicated on their ability to proceed to the selected target sites and remain present in effective concentrations for sufficient periods of time to accomplish the desired therapeutic or diagnostic purpose. Difficulty in achieving efficacy may be exacerbated by the location and environment of the target site as well as by the inherent physical characteristics of the compound administered. For example, drug delivery via routes that are subject to repeated drainage or flushing as part of the body's natural physiological functions offers significant impediments to the effective administration and controlled release of bioactive agents. In this respect, delivery and retention problems are often encountered when administering compounds through the respiratory or gastrointestinal tracts. Repeated administration of fairly large doses are often required to compensate for the amount of drug washed away and to maintain an effective dosing regimen when employing such routes. Moreover, the molecular properties of the bioactive compound may impair the absorption through a given delivery route, thereby resulting in a substantial reduction in efficacy. This is particularly true of lipophilic compounds that are not soluble in aqueous environments (i.e. they are hydrophobic). For instance, insoluble particulates are known to be subject to phagocytosis and pinocytosis, resulting in the accelerated removal of the compound from the target site. Such reductions in delivery and retention time complicate dosing regimes, waste bioactive resources and generally reduce the overall efficacy of the administered drug.
Unlike many hydrophilic compounds, the delivery of lipid soluble or lipophilic drugs by conventional means has been and continues to be problematic. Unfortunately, a number of the most promising therapeutic and diagnostic agents currently under development are relatively insoluble in water. Some are bulky polycyclic molecules whose substantial physical size, coupled with the intrinsic lipophilicity of their molecular structure, has severely limited their use in practical bioactive applications. For instance, the oral administration of lipophilic agents using conventional tablets and capsules suffers the disadvantage of a variable rate of absorption and depends on factors such as the presence or absence of food, the pH of gastrointestinal fluids and gastric emptying rates. Moreover, the degradation of labile drugs by gastric fluids and drug metabolizing enzymes may reduce the drug bioavailability to the point of therapeutic failure.
Other delivery routes fare little better when lipophilic (i.e. hydrophobic) compounds are administered using conventional delivery vehicles. Administration of these water insoluble drugs often requires that they be formulated in the form of hydrocarbon oil in water emulsions or that they be solubilized into a water miscible phase. This suffers drawbacks associated with the formulation of a suitably stable dosage form. For example, the current method used for the intravenous administration of the highly lipophilic cancer drug Taxol involves the use of a polyoxyethylated castor oil vehicle that has been associated with hypersensitivity reactions including dyspnea, bronchospasm, urticaria, and hypotension. In addition, the intravenous administration of drugs such as Taxol, which exhibit high systemic toxicities, severely limits their therapeutic capacity. Thus, despite encouraging results with existing delivery systems, the inherently low bioavailability of these lipophilic compounds at the target site due to inefficient or toxic delivery systems substantially reduces their efficacy.
In spite of the difficulties associated with the delivery of lipophilic drugs, the potential advantages in developing methods to do so are great. Extensive work has been done to show that the membrane permeability, bioavailability and efficacy of drugs often increases with increasing lipophilicity. The development of new systems for the delivery and prolonged release of these compounds could, therefore, significantly increase therapeutic efficacy for the treatment of a wide variety of indications.
In this respect, one class of delivery vehicles that has shown great promise when used for the administration of bioactive agents is fluorochemicals. During recent years, fluorochemicals have found wide ranging application in the medical field as therapeutic agents. The use of fluorochemicals to treat medical conditions is based, to a large extent, on the unique physical and chemical properties of these substances. In particular, the relatively low reactivity of fluorochemicals allows them to be combined with a wide variety of compounds without altering the properties of the incorporated agent. This relative inactivity, when coupled with other beneficial characteristics such as an ability to carry substantial amounts of oxygen, radioopaqueness for certain fluorochemicals and forms of radiation as well as low surface energies, have made fluorochemicals invaluable for a number of therapeutic and diagnostic applications.
For example, various fluorochemical emulsions have been used as oxygen carriers during medical procedures. Conventional fluorochemical-in-water emulsions, which may be infused directly into the blood stream, consist of a selected fluorochemical dispersed in the form of droplets in a continuous aqueous phase. Because of the high oxygen-carrying capacity of fluorochemicals, such emulsions are particularly useful as blood substitutes to provide oxygen to the vascular system. Fluosol.RTM. (Green Cross Corp., Osaka, Japan), a formerly commercially available emulsion containing fluorochemicals, has been used as a gas carrier to oxygenate the myocardium during percutaneous transluminal coronary angioplasty. Fluorochemicals have also been used as contrast enhancement media in radiological imaging (U.S. Pat. No. 3,975,512) and in nuclear magnetic resonance imaging (U.S. Pat. No. 5,114,703). A fluorochemical emulsion is currently being investigated as a means of expanding the efficacy of perioperative hemodilution and reducing the need for homologous blood transfusion. Other proposed medical uses include the treatment of cardiovascular and cerebrovascular diseases, organ preservation and cancer therapy; diagnostic ultrasound imaging and veterinary therapy.
In addition to traditional fluorochemical-in-water emulsions, other fluorochemical systems have been examined for utility under a variety of conditions. For example, it has been shown that water-in-fluorochemical reverse emulsions may be stabilized through the selection of appropriate emulsifiers and used as drug delivery vehicles. Such systems have been reported as being useful.
Yet, despite these advancements there still remains a substantial need for delivery vehicles that may be used for the effective administration of hydrophobic bioactive agents. Similarly, it is often desirable to administer both hydrophobic and hydrophilic compounds simultaneously using the same vehicle comprising a hydrophobic continuous phase.
Accordingly, it is an object of the present invention to provide multiple emulsions capable of incorporating therapeutic or diagnostic compounds which exhibit improved shelf-lives and stability.
It is a further objective of the present invention to provide bioactive preparations capable of simultaneously delivering both lipophilic and hydrophilic bioactive agents while allowing improved control over release of both compounds.
It is yet a further objective of the present invention to provide methods for the formation and delivery of multiple emulsions comprising bioactive agents exhibiting enhanced bioavailability.